Sleep apnea is generally defined as an intermittent cessation of airflow at the nose and mouth during sleep. Continuous periods of apnea are termed apneic events. Their duration may vary but by convention, apneic events of at least 10 seconds in duration are considered significant. However, apneic events may extend up to 2-3 minutes and may cause complete (apnea) or partial (hypopnea) cessation of airflow. In this application the term apnea comprises hypopnea, and the term apneic event comprises hypopneic event. Apneic events, including hypopneic events, may also occur in aggregated form or appear in a complex with a general reduction of ventilation thereby generating continuous or sustained hypoventilation. This condition, in the context of the present invention, excludes obstruction by foreign objects or by material excreted by the body, such as mucus. Sleep apneas have been classified into three different types; central, obstructive and mixed. Central sleep apnea (CSA) is characterized by complete cessation of the activity of all respiratory muscles while in obstructive sleep apnea (OSA) airflow is interrupted despite continuing respiratory neural drive. OSA occurs as a result of occlusion of the upper airway, usually at the level of the oropharynx, and is the most prevalent form of sleep apnea. Mixed apnea consists of an initial central component followed by obstructive apnea. In the following CSA will not be differentiated from OSA, and will be comprised by the term OSA.
OSA spans over a wide range of upper airway flow changes with the common denominator of one or more of the following; arousal (brief awakening from sleep), alteration of tissue blood gas and pH content as well as endocrine, paracrine, hemodynamic and vascular changes. In its simplest form the condition may be characterized by subtle airflow restriction typically associated with sleep fragmentation resulting in daytime sleepiness or various degree of cognitive dysfunction as well as various symptoms suggestive on non-restorative sleep. OSA associated with daytime symptoms, specifically daytime hypersomnolence, is generally referred to as the Obstructive Sleep Apnea Syndrome (OSAS). Beside hypersomnolence, cognitive and mood changes appear to provide a substantial burden on general health in this condition. Hypersomnolence has been associated with complications including reduced working and driving performance. Moreover, cardiovascular complications, in particular hypertension, cardiac failure, myocardial infarction and stroke are common in OSA and OSA has been associated with increased insulin resistance, diabetes, obesity, changes in lipid metabolism and increased platelet aggregability. Such symptoms and complications are not confined to severe cases but also observed in cases of partial OSA and in OSA patients without apparent signs of daytime hypersomnolence.
The prevalence of OSA in the adult population depends on clinical laboratory cut-off values applied for the condition. Epidemiological studies suggest that OSA defined as an apnea-hypopnea index (number of apneas per hour of sleep) equal to or higher than 5 occurs in 24% of working adult men and in 9% of adult women. The prevalence of OSA in combination with pronounced daytime symptoms (OSAS) was observed at a rate of 4% in men and 2% in women. The prevalence of minor daytime symptoms induced by discrete sleep-related breathing disturbances is unknown. However, habitual snoring is a common phenomenon reported by 15-25% of the adult population. The patho-physiology of OSA is virtually unknown.
The principal forms of treating or preventing OSA include surgery of the upper airway, intra-oral mandibular advancement devices and long-term treatment with positive airway pressure (PAP). PAP treatment operates by the generation of a mechanical airway splint counteracting airway collapse. Although technically effective this method is hampered by poor long-term compliance due to poor tolerance and frequent side effects from airway mucous membranes. Surgery and intra-oral mandibular advancement devices are not uniformly effective. In particular surgery has been associated with a considerable relapse of symptoms also in cases with initially excellent treatment results. Various forms of pharmacological treatment, e.g. acetazolamide, tricyclic antidepressants, theophylline, progesterone, and topiramate have been employed but have not gained wide clinical use.
Thus there is a need for an improved method for treating or preventing snoring, sleep apnea and other forms of sleep disordered breathing. In particular, pharmacological treatment of such disorders would offer a definite advantage in front the invasive or non-invasive methods used at present, many of which only provide insufficient relief and some of which are cumbersome to the patient.
Zonisamide, 1,2-benzisoxazole-3-methanesulfonamide, disclosed in U.S. Pat. No. 4,513,006 is a known anti-epileptic drug; see: Peters D H and Sorkin E M. Zonisamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 45(5); 1993:760-87. It has also been considered as a potential anti-obesity agent and as an agent for treating neuropathic pain (U.S. Pat. No. 4,689,350). Its potential effect in the treatment of Parkinson's disease is presently investigated in clinical trials.